Nrf1 and Nrf2 Play Distinct Roles in Activation of Antioxidant Response Element-dependent Genes
Nrf1 and Nrf2 Play Distinct Roles in Activation of Antioxidant Response Element-dependent Genes
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DOI：
10.1074/jbc.m804597200
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发表时间：
2008-11-28
影响因子：
4.8
通讯作者：
Yamamoto, Masayuki
中科院分区：
文献类型：
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作者：
Ohtsuji, Makiko;Katsuoka, Fumiki;Yamamoto, Masayuki
Nrf 1是脊椎动物Cap 'n'Collar（CNC）转录因子家族的成员，通常包含独特的碱性亮氨酸拉链结构域。在CNC家族成员中，已知Nrf 2通过抗氧化反应元件（ARE）调节一系列抗氧化剂和外源性代谢酶基因。尽管Nrf 1也被证明与ARE结合，但尚不清楚它在调节具有该元件的基因方面是否发挥与Nrf 2不同的作用。为了在体内解决这个问题，我们产生了携带肝细胞特异性破坏Nrf 1基因的小鼠。虽然Nrf 2基因敲除小鼠在非应激条件下未表现出肝损伤，但肝细胞特异性Nrf 1缺失引起的肝损伤类似于人类疾病非酒精性脂肪性肝炎。基因表达分析显示，Nrf 1的破坏导致应激，以Nrf 2依赖的方式激活许多ARE驱动的基因，这表明Nrf 2不能完全补偿肝脏中Nrf 1功能的丧失。与此相反，金属硫蛋白-1和-2（MT 1和MT 2）基因的表达，其中每一个港口至少有一个ARE在其调控区，减少在Nrf 1-null突变小鼠。而Nrf 1和Nrf 2结合的MT 1 ARE具有可比的亲和力，Nrf 1优先激活报告基因的表达，通过MT 1 ARE。因此，这项研究确定了第一个完全依赖于Nrf 1的ARE依赖性基因，这表明它在调节ARE驱动的基因中起着独特的功能作用。
Nrf1 is a member of the vertebrate Cap'n'Collar (CNC) transcription factor family that commonly contains a unique basic-leucine zipper domain. Among CNC family members, Nrf2 is known to regulate a battery of antioxidant and xenobiotic-metabolizing enzyme genes through the antioxidant response element (ARE). Although Nrf1 has also been shown to bind the ARE, it is unclear whether it plays a distinct role from Nrf2 in regulating genes with this element. To address this issue in vivo, we generated mice bearing a hepatocyte-specific disruption of the Nrf1 gene. Although Nrf2 knock-out mice did not exhibit liver damage when they were maintained in an unstressed condition, hepatocyte-specific deletion of Nrf1 caused liver damage resembling the human disease non-alcoholic steatohepatitis. Gene expression analysis revealed that the disruption of Nrf1 causes stress that activates a number of ARE-driven genes in an Nrf2-dependent manner, indicating that Nrf2 cannot compensate completely for loss of Nrf1 function in the liver. In contrast, expression of metallothionein-1 and -2 (MT1 and MT2) genes, each of which harbors at least one ARE in its regulatory region, was decreased in the Nrf1-null mutant mice. Whereas Nrf1 and Nrf2 bound the MT1 ARE with comparable affinity, Nrf1 preferentially activated the reporter gene expression through the MT1 ARE. This study has, thus, identified the first ARE-dependent gene that relies exclusively on Nrf1, suggesting that it plays a distinct functional role in regulating ARE-driven genes.